Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade

Abstract

The outcome for patients with lung cancer has not changed significantly for more than two decades. Several studies show that the overexpression of vascular endothelial growth factor (VEGF)/vascular permeability factor and epidermal growth factor (EGF) and their receptors correlates with the clinical outcome for lung cancer patients. However, clinical trials of agents that target either of these pathways alone have been disappointing. We hypothesize that targeting both the tumor and its vasculature by simultaneously blocking the VEGFR and EGFR pathways will improve the treatment of locoregional lung cancer. Human lung cancer specimens were first examined for the activation of VEGF receptor 2 (VEGFR2) and EGF receptor (EGFR) for tumor and tumor-associated endothelial cells, and both were found to be activated. The effects of ZD6474 (ZACTIMA), a small-molecule inhibitor of VEGFR2 and EGFR tyrosine kinases, were then studied in vitro using human lung cancer and microvascular endothelial cells. In vitro, ZD6474 inhibited EGFR, VEGFR2, mitogenactivated protein kinase and Akt phosphorylation, EGF-and VEGF-induced proliferation, and endothelial cell tube formation and also induced apoptosis. ZD6474 was further studied in vivo using an orthotopic mouse model of nonsmall cell lung cancer using NCI-H441 human lung adenocarcinoma cells. The inhibition of both VEGFR2 and EGFR signaling pathways by ZD6474 resulted in profound antiangiogenic, antivascular, and antitumor effects. These results provide a basis for the development of clinical strategies for the combination of selective protein tyrosine kinase inhibitors that block both EGFR and VEGFR signaling as part of the management of locally advanced lung cancer. [Mol Cancer Ther 2007;6(2):471 -83]

Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma

“…Accordingly, we selected three histologic subtype human STS cell lines: SKLMS1 (leiomyosarcoma), HT1080 (fibrosarcoma), and MES-SA (uterine sarcoma). Vandetanib inhibits VEGFR2 and EGFR phosphorylation (15,16); using Western immunoblotting, we evaluated the expression of these tyrosine kinase targets in the selected cell lines (Fig. 1A).…”

Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in ApcMin/+ mice

“…In the current study, strong phospho-EGFR activity was seen on the cell membrane and was dramatically reduced by ZD6474. Because of the technical limitations of the available antibodies, it is currently only possible to determine phospho-VEGFR2 levels by immunohistochemistry in situations where there is a high level of activity of the receptor, such as the lung, where inhibition of phospho-VEGFR2 by ZD6474 has been shown (43). The expression levels of VEGFR2 and pVEGFR2 in the intestinal epithelia are relatively low (41).…”

Inhibition of Tumor Growth and Metastasis in Non–Small Cell Lung Cancer by LY2801653, an Inhibitor of Several Oncokinases, Including MET

“…The reverse-phase protein microarray (RPMA) was conducted at Theranostics Health Inc. as previously described (16 For the orthotopic model of NSCLC cells, logarithmically growing H441, H460, A549, and H1299 tumor cells (>95% viability) at 1 Â 10 6 or 2 Â 10 6 cells in 55 mL containing 50 mg Matrigel (BD Biosciences) were injected into the left lung lobe of mice as previously described (14). Seven days postimplantation, 2 mice were sacrificed to confirm the growth of the primary lung tumor (2 Â 2 mm 2 ) and the remaining mice were randomized into various groups (n ¼ 8-10) and treated with LY2801653.…”

“…Given the potential importance of MET signaling in tumor biology, we sought disease-relevant models to evaluate the potential use of MET inhibitors in NSCLCs. Orthotopic lung cancer models were developed to recapitulate the local and metastatic patterns seen in patients with lung cancer in addition to NSCLC patientderived tumor (PDT) xenograft models (14,15). In orthotopic models, single solid primary lung tumors progress to a widespread and fatal state characterized by the dissemination of the primary tumor to regional lymph nodes and the ipsilateral chest wall.…”